Amide-directed Rhodium(III)-catalyzed C4—H Alkenylation of Indoles with gem-Difluoromethylene Alkynes

Abstract

The direct and selective C4—H functionalization of indoles remains a significant synthetic challenge. Addressing this, we disclose a highly efficient Rh(III)-catalyzed C4—H alkenylation of indoles employing gem-difluoromethylene alkynes. This directing group-assisted protocol delivers valuable difluorinated indole derivatives in excellent yields (up to 88%), with a broad substrate scope and exceptional functional group tolerance, providing a practical and versatile route for appealing indole diversification.

Keywords

C—H activation / Indole / Rhodium catalysis / gem-Difluoromethylene alkyne

References

[1] Stempel E, Gaich T. Acc. Chem. Res.. 2016, 492390.

[2] Zhang M Z, Chen Q, Yang G F. Eur. J. Med. Chem.. 2015, 89421.

[3] Kochanowska-Karamyan A J, Hamann M T. Chem. Rev.. 2010, 1104489.

[4] Corsello M A, Kim J, Garg N K. Chem. Sci.. 2017, 85836.

[5] Chen J B, Jia Y X. Org. Biomol. Chem.. 2017, 153550.

[6] Cacchi S, Fabrizi G. Chem. Rev.. 2005, 1052873.

[7] Humphrey G R, Kuethe J T. Chem. Rev.. 2006, 1062875.

[8] Zeng W, Han C, Mohammed S, Li S, Song Y, Sun F, Du Y. RSC Med. Chem.. 2024, 15788.

[9] Leitch J A, Bhonoah Y, Frost C G. ACS Catal.. 2017, 75618.

[10] Kalepu J, Gandeepan P, Ackermann L, Pilarski L T. Chem. Sci.. 2018, 94203.

[11] Shah T A, De P B, Pradhan S, Punniyamurthy T. Chem. Commun.. 2019, 55572.

[12] Chen X, Zheng G, Li Y, Song G, Li X. Org. Lett.. 2017, 196184.

[13] Biswas A, Samanta R. Eur. J. Org. Chem.. 2018, 20181426.

[14] Lanke V, Bettadapur K R, Prabhu K R. Org. Lett.. 2016, 185496.

[15] Liu Q, Li Q, Ma Y, Jia Y. Org. Lett.. 2013, 154528.

[16] Thakur R, Luxami V, Paul K. Chem. Commun.. 2025, 6114374.

[17] Liu X, Li G, Song F, You J. Nat. Commun.. 2014, 55030.

[18] Zhou T, Li B, Wang B. Chem. Commun.. 2017, 536343.

[19] Yang Y, Gao P, Zhao Y, Shi Z. Angew. Chem. Int. Ed.. 2017, 563966.

[20] Borah A J, Shi Z. Chem. Commun.. 2017, 533945.

[21] Lanke V, Prabhu K R. Chem. Commun.. 2017, 535117.

[22] Chen S, Feng B, Zheng X, Yin J, Yang S, You J. Org. Lett.. 2017, 192502.

[23] Maity S, Karmakar U, Samanta R. Chem. Commun.. 2017, 5312197.

[24] Liu Q, Li Q, Ma Y, Jia Y. Org. Lett.. 2013, 154528.

[25] Wu Q, Gao P, Yuan Y. Asian J. Org. Chem.. 2021, 10749.

[26] Sandeep K, Kumar A S, Kumara Swamy K C. Eur. J. Org. Chem.. 2022, 2022e202201037.

[27] Lv J, Wang B, Yuan K, Wang Y, Jia Y. Org. Lett.. 2017, 193664.

[28] Okada T, Sakai A, Hinoue T, Satoh T, Hayashi Y, Kawauchi S, Chandrababunaidu K, Miura M. J. Org. Chem.. 2018, 835639.

[29] Kona C N, Nishii Y, Miura M. Org. Lett.. 2018, 204898.

[30] Banjare S K, Nanda T, Pati B V, Adhikari G K D, Dutta J, Ravikumar P C. ACS Catal.. 2021, 1111579.

[31] RaziullahKumar M, Rastogi A, Ahmad A, Koley D. Adv. Synth. Catal.. 2025, 367e202400863.

[32] Rastogi A, Shaw A K, Kumari S, Kant R, Koley D. Org. Lett.. 2025, 275281.

[33] Lanke V, Ramaiah Prabhu K. Org. Lett.. 2013, 156262.

[34] Li L, Zhong X, Xu J, Gao H, Zhou Z, Yi W. Adv. Synth. Catal.. 2021, 3631352.

[35] Wang CQ, Zhang Y, Feng C. Angew. Chem. Int. Ed.. 2017, 5614918.

[36] Gao H, Lin S, Zhang S, Chen W, Liu X, Yang G, Lerner R A, Xu H, Zhou Z, Yi W. Angew. Chem. Int. Ed.. 2021, 601959.

[37] Lin S, Wang Y, Peng Z H, Li Y, Zhou Z, Gao H, Yi W. Asian J. Org. Chem.. 2022, 11e202200019.

[38] Luo W, Zhang C, Dong L. J. Org. Chem.. 2024, 899627.

[39] Yang J, Shi W, Chen W, Gao H, Zhou Z, Yi W. J. Org. Chem.. 2021, 869711.

[40] Gao H, Sun M, Zhang H, Bian M, Wu M, Zhu G, Zhou Z, Yi W. Org. Lett.. 2019, 215229.

[41] Wang T, Peng ZH, Wu L, Song Q, Li Q, Gao H, Zeng Z, Zhou Z, Yi W. Org. Chem. Front.. 2023, 105916.

[42] Romanov-Michailidis F, Ravetz B D, Paley D W, Rovis T. J. Am. Chem. Soc.. 2018, 1405370.

[43] Zeng Z, Xu H, Gao H, Zhou Z, Yi W. Coord. Chem. Rev.. 2025, 522216244.

[44] Simmons E M, Hartwig J F. Angew. Chem. Int. Ed.. 2012, 513066.

[45] Wu X, Ji H. J. Org. Chem.. 2018, 834650.

[46] Yang Y, Li N, Zhao J, Jiang Y, Zhang X, Fan X. Adv. Synth. Catal.. 2021, 3633600.

[47] Li T, Yang Z, Song Z, Chauvin R, Cui X. Org. Lett.. 2020, 224078.

RIGHTS & PERMISSIONS

Jilin University, The Editorial Department of Chemical Research in Chinese Universities and Springer-Verlag GmbH